> For the complete documentation index, see [llms.txt](https://www.parapathology.com/llms.txt). Markdown versions of documentation pages are available by appending `.md` to page URLs; this page is available as [Markdown](https://www.parapathology.com/clippings/emerging-concepts-and-recent-advances-in-renal-cell-neoplasia.md). # Emerging concepts and recent advances in renal cell neoplasia Guest editorial in Virchows Archiv by Kiril Trpkov and Abbas Agaimy highlighting emerging concepts and taxonomic evolution in renal cell neoplasia: consolidating renal hemangioblastoma (RHB) into the ### Summary A state-of-the-art guest editorial by **Kiril Trpkov** (University of Calgary / Alberta Precision Labs) and **Abbas Agaimy** (Erlangen University Hospital, Friedrich Alexander University) published in *Virchows Archiv* (DOI: [10.1007/s00428-026-04695-9](https://doi.org/10.1007/s00428-026-04695-9)). The editorial introduces a dedicated special issue on renal cell neoplasia, capturing the rapid evolution from morphology-exclusive categorization toward integrated molecular-morphologic definitions. Trpkov & Agaimy synthesize key multi-institutional findings that challenge prevailing dogmas in the **WHO 2022 (5th edition)** classification of renal tumors: 1. **Renal Hemangioblastoma (RHB) is not a distinct entity:** Multi-institutional histopathologic, immunohistochemical, and molecular data demonstrate that RHB is a specialized morphological pattern within the spectrum of **renal cell carcinoma with fibromyomatous stroma (RCC-FMS)**, driven by TSC/mTOR alterations. The authors advocate formally eliminating RHB as an autonomous entity in the next WHO edition. 2. **Aggressive non-conventional FLCN-mutated renal tumors:** Long considered indolent "hybrid" oncocytic tumors occurring in Birt-Hogg-Dubé (BHD) syndrome, *FLCN*-deficient renal neoplasms can manifest as high-grade tubulopapillary/solid carcinomas with lethal metastatic potential. 3. **Malignant potential in TSC/mTOR-mutated eosinophilic RCCs:** While low-grade oncocytic tumor (LOT) and eosinophilic vacuolated tumor (EVT) run an indolent course, *MTOR*-mutated tumors harboring **monosomy/loss of chromosome 1** exhibit distant metastasis. 4. **Autonomous status of Papillary Renal Neoplasm with Reverse Polarity (PRNRP):** PRNRP possesses a distinct genotype (*KRAS* exon 2 mutations, lack of trisomies 7/17), distinct immunophenotype (GATA3+, L1CAM+), and uniform indolent behavior, arguing for its separation from conventional papillary RCC. 5. **GPR143 as a companion biomarker:** An MiT-regulated transmembrane protein providing superior sensitivity over GPNMB for detecting FLCN/TSC/mTOR-TFE3/TFEB alterations. 6. **Real-world gaps in SDH- and FH-deficient RCC:** Uneven laboratory access to 2SC and SDHB immunohistochemistry across tertiary pathology services underscores the urgency for centralized reference testing and molecular tumor boards. *** ### Key Taxonomic Shifts & Methodological Insights #### 1. Consolidating Renal Hemangioblastoma into RCC with Fibromyomatous Stroma Historically described by Canzonieri et al. in 1993 as "mixed renal tumor with carcinomatous and fibroleiomyomatous components", RCC with fibromyomatous stroma (RCC-FMS) has carried confusing nomenclature (RCC with leiomyomatous stroma, *TCEB1*/ELOC-mutated RCC, TSC-associated RCC). * **The Hemangioblastoma Overlap:** Recent multi-institutional studies by Zhao et al. and a critical review by Baranova & Trpkov demonstrate that tumors diagnosed as "pure renal hemangioblastoma" (RHB) or exhibiting hemangioblastoma-like vascular/stromal areas share identical: * Clinical profiles (indolent behavior, sporadic or syndromic Tuberous Sclerosis Complex). * Immunophenotypic profiles (positivity for CD10, CK, vimentin, S100/inhibin variable). * Molecular alterations (**TSC1, TSC2, or MTOR mutations**). * **Distinction from CNS Hemangioblastoma:** Unlike CNS hemangioblastoma (which is driven by *VHL* inactivation and associated with von Hippel-Lindau disease), renal hemangioblastoma-like lesions belong to the **TSC/mTOR pathway-altered RCC-FMS continuum**. * **Taxonomic Resolution:** Trpkov & Agaimy recommend formally retiring RHB as a stand-alone entity and recognizing it as a morphologic variant within RCC-FMS in future classifications. ``` Renal Hemangioblastoma vs. RCC-FMS: The Paradigm Shift ┌──────────────────────────────────────────────┐ │ Historical Schema: │ │ - Renal Hemangioblastoma (Separate entity?) │ │ - RCC with Leiomyomatous/Fibromyomatous │ │ Stroma (Separate entity?) │ └──────────────────────────────────────────────┘ ▼ ┌──────────────────────────────────────────────┐ │ Unified Modern Continuum (Trpkov 2026): │ │ RCC with Fibromyomatous Stroma (RCC-FMS) │ │ ├── Classic epithelial nests + smooth muscle│ │ └── Hemangioblastoma-like pattern (RHB) │ │ Driven by: TSC/mTOR pathway alterations │ │ Behavior: Indolent │ └──────────────────────────────────────────────┘ ``` *** #### 2. FLCN-Mutated Renal Tumors: The Emergence of Aggressive High-Grade Phenotypes Germline mutations in *FLCN* (encoding folliculin) cause Birt-Hogg-Dubé (BHD) syndrome, predisposing patients to pulmonary cysts, spontaneous pneumothorax, cutaneous fibrofolliculomas, and multifocal renal tumors. Somatic biallelic *FLCN* mutations also occur sporadically. * **The Classical "Conventional" Phenotype:** Solid or nested architecture composed of an intimate mosaic of pale, clear cells and eosinophilic oncocytic cells, low nuclear grade, and indolent long-term behavior. * **The Newly Documented "Non-Conventional" Aggressive Phenotype:** * **Siegmund et al. (doi: 10.1007/s00428-026-04588-x):** Identified *FLCN*-mutated cases showing tubulocystic and tubulopapillary patterns with advanced pathologic stage and distant metastasis. * **Wang et al. (doi: 10.1007/s00428-026-04693-x):** Reported 6 *FLCN*-mutated high-grade RCCs with non-conventional papillary/tubulopapillary and solid features; **3 developed distant metastases, and 2 succumbed to disease**. * **Diagnostic Alert for Surgical Pathologists:** High-grade papillary renal tumors that do not match classic papillary RCC or FH-deficient RCC should undergo targeted *FLCN* molecular analysis. *** #### 3. Aggressive Subset within TSC/mTOR-Altered Eosinophilic Tumors The expanding group of eosinophilic/oncocytic renal tumors includes: * **Low-grade oncocytic tumor (LOT):** Diffuse strong CK7+, CD117 negative, *TSC1/TSC2* mutated, completely indolent. * **Eosinophilic vacuolated tumor (EVT):** Large cytoplasmic vacuoles, prominent round nucleoli, CD117+, CK7 negative/focal, *TSC2/MTOR* mutated, completely indolent. * **Eosinophilic solid and cystic (ESC) RCC:** Female predominance, *TSC1/TSC2* mutated, indolent in most cases. **The Metastatic Outlier:** Kwon et al. (doi: 10.1007/s00425-025-04363-4) reported two cases of ***MTOR*****-mutated eosinophilic RCCs with monosomy / loss of chromosome 1** that presented with distant metastatic dissemination. This proves that eosinophilic tumors with mTOR hyperactivation are not universally benign; concurrent chromosomal losses (specifically chromosome 1) can herald aggressive systemic progression. *** #### 4. Papillary Renal Neoplasm with Reverse Polarity (PRNRP) In the 2022 WHO classification, PRNRP was categorized merely as an eosinophilic variant/pattern of papillary RCC. Marletta et al. (doi: 10.1007/s00428-026-04536-9) performed a comparative multi-platform analysis of 15 PRNRPs versus 16 eosinophilic oncocytic papillary RCCs (E/OPRCC): | Feature | Papillary Renal Neoplasm with Reverse Polarity (PRNRP) | Conventional / Eosinophilic Papillary RCC | | ----------------------- | --------------------------------------------------------------------------------------------- | ------------------------------------------ | | **Nuclear Orientation** | Reversed / Apical (nuclei line up along the luminal surface, away from the basement membrane) | Basal or haphazard (pseudostratified) | | **Nuclear Grade** | Uniformly low-grade (round, inconspicuous nucleoli) | Variable (low to high WHO/ISUP grade) | | **GATA3 IHC** | **Uniformly positive (diffuse, strong nuclear)** | Negative | | **L1CAM IHC** | **Positive** | Typically negative | | **Cytogenetics** | **No trisomy 7 or 17** | **Trisomy 7 and 17 (hallmark)** | | **Driver Mutation** | **Recurrent *****KRAS***** exon 2 mutations (e.g. G12D, G12V)** | *MET* mutations / chromosome 7 gain | | **Clinical Behavior** | **Uniformly indolent** (zero metastases reported) | Variable; significant metastatic potential | Trpkov & Agaimy conclude that PRNRP fulfills all criteria of an autonomous, biologically distinct low-grade renal neoplasm. *** #### 5. GPR143: Next-Generation Companion Biomarker to GPNMB * **The Problem with GPNMB:** Glycoprotein nonmetastatic melanoma protein B (GPNMB) is an established marker for tumors driven by TFE3/TFEB fusions or FLCN/TSC/mTOR activation. However, GPNMB interpretation can suffer from patchy reactivity, variable background, and lower sensitivity in borderline cases. * **The Solution (Li et al., doi: 10.1007/s00428-026-04646-4):** **GPR143** is a transmembrane protein regulated by MiT transcription factors (TFE3, TFEB). GPR143 demonstrated **diffuse immunoreactivity in FLCN-, TSC-, mTOR-, and TFE3/TFEB-altered renal tumors**, maintaining strong expression even in cases with negative or focal GPNMB staining. *** #### 6. Overcoming Real-World Diagnostic Barriers in SDH- and FH-Deficient RCC Fumarate hydratase (FH)-deficient RCC and Succinate dehydrogenase (SDH)-deficient RCC are critical diagnoses due to high lethality (FH-deficient) and syndromic germline inheritance (HLRCC, Carney-Stratakis syndrome). Fanelli et al. (doi: 10.1007/s00428-026-04431-3) surveyed pathology laboratories across Italy (GIUP study): * **Diagnostic Trigger:** Most pathologists identify these tumors through morphologic suspicion (e.g., prominent viral inclusion-like eosinophilic nucleoli with perinucleolar halos for FH; pale eosinophilic cytoplasm with flocculent inclusions for SDH). * **The Bottleneck:** Severe laboratory disparities in testing access. Confirmatory **2SC (S-\[2-succino]-cysteine)** IHC and **SDHB** IHC, along with germline/somatic NGS, are restricted to specialized academic centers. * **Action Plan:** Development of standardized regional hub-and-spoke networks, reflex testing cascades, and mandatory referral to molecular tumor boards. *** ### Why It Matters for Digital & Computational Pathology 1. **Re-Evaluating the \[\[PinkKidney]] Binary Classification:** The group's `PinkKidney` project focuses on separating chromophobe RCC from oncocytoma using tile embeddings from foundation models (UNI, Virchow) and multiple-instance learning (MIL). * Trpkov & Agaimy show that the oncocytic space contains multiple intermediate and emerging entities (LOT, EVT, FLCN-driven tumors, and MTOR-mutated aggressive RCC). * Computational models must be stress-tested against these non-binary diagnostic confounders to evaluate out-of-distribution robustness. 2. **Quantitative Morphometry of Reverse Nuclear Polarity:** Reversed polarity in PRNRP is a spatial geometric feature. Cell instance segmentation models (e.g. InstanSeg, StarDist in QuPath) can directly quantify the distance of the nuclear centroid relative to the apical border versus the basement membrane, transforming a subjective visual criterion into an objective metric. 3. **Automated Scoring of Novel Biomarkers:** Evaluating membranous GPR143 and cytoplasmic GPNMB via automated QuPath cell classification can streamline multi-marker triage for ambiguous eosinophilic tumors.